SARS-CoV-2 evolved variants optimize binding to cellular glycocalyx
Year: 2023
Type: article
Abstract: The SARS-CoV-2 Omicron sub-lineage contains a significant number of mutations in the spike protein relative to earlier SARS-CoV-2 variants. Most notably, these mutations significantly increased the positive charge of the spike protein that is postulated to confer increased infectivity, potentially through enhanced interactions with cell surface receptors, and an altered host-cell entry mechanism. While heparan sulfate (HS) was shown to be a key co-receptor in the host-cell entry of SARS-CoV-2, the effect of spike charge on its interactions with heparan sulfate has not been clearly elucidated. Here, we investigate the role of evolving spike positive charge in accelerating long-range interactions to heparan sulfate and ACE2 in the glycocalyx. We show that the positively charged Omicron evolved enhanced binding rates to the negatively charged glycocalyx. Moreover, we discovered that while the Omicron spike-ACE2 affinity is comparable to Delta, the Omicron spike interactions with heparan sulfate are significantly enhanced, giving rise to a ternary complex of spike-HS-ACE2 with a larger proportion of double-bound and triple-bound ACE2. Our findings suggest that SARS-CoV-2 variants evolve to be more dependent on heparan sulfate in viral attachment and infection. We leveraged this understanding for the successful and sensitive detection of the Omicron variant. The evolving enhanced binding of SARS-Cov-2 to heparan sulfate presents new therapeutic and diagnostic opportunities.
Source: Cell Reports Physical Science
Language: English
Subfield: Infectious Diseases
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $5,460
Funders: National Science Foundation, Research Corporation for Science Advancement, University of North Carolina, University of Texas at Austin, San Diego Supercomputer Center, North Carolina General Assembly, Moores Cancer Center, UC San Diego Health, National Institutes of Health, Directorate for Biological Sciences, Directorate for Mathematical and Physical Sciences, Department of Mechanical Engineering, University of Texas at Austin, University of North Carolina at Chapel Hill, University of California, San Diego, National Institute of General Medical Sciences, National Institute of Allergy and Infectious Diseases, National Institute of Biomedical Imaging and Bioengineering
Awards: Midwest AViDD Center, RAPID: A Lung Mucus Strategy for COVID-19 Viral Protection, G4599449788, A MULTISCALE APPROACH TO TARGET THE ACHILLES HEEL OF P53 CANCER MUTANTS, G5799569228, G5803820641, G7056887998, G7249180383, RAPID: Understanding the Effects of Glycosylation on Spike Vulnerabilities and the Host Range of SARS-CoV-2, Training in Multi-scale Analysis of Biological Structure and Function
OpenAlex ID: W4362696962